Uncontrolled inflammation is a leading cause of many clinically relevant diseases. Current therapeutic strategies focus mainly on immunosuppression rather than on the mechanisms of inflammatory resolution. Glucocorticoids (GCs) are still the most widely used anti-inflammatory drugs. GCs affect most immune cells but there is growing evidence for cell type specific mechanisms. Different subtypes of monocytes and macrophages play a pivotal role both in generation as well as resolution of inflammation. Activation of these cells by microbial products or endogenous danger signals results in production of pro-inflammatory mediators and initiation of an inflammatory response. GCs efficiently inhibit these processes by down-regulating pro-inflammatory mediators from macrophages and monocytes. On the other hand, GCs act on “naïve” monocytes and macrophages and induce anti-inflammatory mediators and differentiation of anti-inflammatory phenotypes. GC-induced anti-inflammatory monocytes have an increased ability to migrate toward inflammatory stimuli. They remove endo- and exogenous danger signals by an increased phagocytic capacity, produce anti-inflammatory mediators and limit T-cell activation. Thus, GCs limit amplification of inflammation by repressing pro-inflammatory macrophage activation and additionally induce anti-inflammatory monocyte and macrophage populations actively promoting resolution of inflammation. Further investigation of these mechanisms should lead to the development of novel therapeutic strategies to modulate undesirable inflammation with fewer side effects via induction of inflammatory resolution rather than non-specific immunosuppression.

To decipher early promoters of the local microenvironment for Th2‐type immunity, we wanted to identify gene patterns that were induced by Leishmania major in the infected skin of susceptible, Th2‐prone BALB/c, but not of resistant, Th1‐prone C57BL/6 mice. We found a marked up‐regulation of the chemokine I‐TAC (Cxc111) during the first 2 d of infection in the epidermis of susceptible but not of resistant mice. Accordingly, local injection of I‐TAC (2×1 μg) in resistant mice on the first day of infection resulted in a Th2‐driven, sustained deterioration of disease and dramatically enhanced parasite levels. On the cellular level, I‐TAC decreased IL‐12 production by dendritic cells (DCs) in skin‐draining lymph nodes and by DCs in vitro . Thus, we demonstrate for the first time that epidermis‐derived I‐TAC triggers a sustained Th2‐response that determines the outcome of a complex immunological process.—Roebrock, K., Sunderkotter, C., Münck, N‐A., Wolf, M., Nippe, N., Barczyk, K., Varga, G., Vogl, T., Roth, J., Ehrchen, J. Epidermal expression of I‐TAC (Cxc111) instructs adaptive Th2‐type immunity. FASEB J. 28, 28–1724 (1734). www.fasebj.org

Gastroesophageal reflux disease (GERD) occurs frequently in patients with SSc. We investigated whether the presence of GERD and/or the use of anti-acid therapy, specifically proton-pump inhibitors (PPIs), are associated with long-term outcomes, especially in SSc-associated interstitial lung disease (SSc-ILD). We retrospectively analysed patients with SSc and SSc-ILD from the German Network for Systemic Sclerosis (DNSS) database (2003 onwards). Kaplan–Meier analysis compared overall survival (OS) and progression-free survival (PFS) in patients with GERD vs without GERD (SSc and SSc-ILD), and PPI vs no PPI use (SSc-ILD only). Progression was defined as a decrease in either percentage predicted forced vital capacity of ≥10% or single-breath diffusing capacity for carbon monoxide of ≥15%, or death. It was found that 2693/4306 (63%) registered patients with SSc and 1204/1931 (62%) with SSc-ILD had GERD. GERD was not associated with decreased OS or decreased PFS in patients in either cohort. In SSc-ILD, PPI use was associated with improved OS vs no PPI use after 1 year [98.4% (95% CI: 97.6, 99.3); n = 760 vs 90.8% (87.9–93.8); n = 290] and after 5 years [91.4% (89.2–93.8); n = 357 vs 70.9% (65.2–77.1); n = 106; P < 0.0001]. PPI use was also associated with improved PFS vs no PPI use after 1 year [95.9% (94.6–97.3); n = 745 vs 86.4% (82.9–90.1); n = 278] and after 5 years [66.8% (63.0–70.8); n = 286 vs 45.9% (39.6–53.2); n = 69; P < 0.0001]. GERD had no effect on survival in SSc or SSc-ILD. PPIs improved survival in patients with SSc-ILD. Controlled, prospective trials are needed to confirm this finding.

Summary: Background and objectives: Erysipelas, caused by beta‐hemolytic streptococci, and limited cellulitis, frequently caused by Staphylococcus aureus or other bacteria, are skin and soft tissue infections characterized by typical clinical signs. However, despite the therapeutical relevance they are often not differentiated (e.g in clinical trials). Erysipelas are efficiently treated with penicillin, while limited cellulitis is treated with more wide‐spectrum antibiotics. This study investigates whether parameters such as CRP, blood counts or novel parameters like immature granulocytes could serve as biomarkers to distinguish between these entities.Patients and methods: For this retrospective analysis 163 patients were included. We compared laboratory markers in patients with erysipelas (n = 68) to those with limited cellulitis (n = 41) of the leg. Both erysipelas and limited cellulitis were defined clinically, with an additional aspect for erysipelas being a prompt response to penicillin.Results: Erysipelas were characterized by higher levels of inflammation. CRP and leukocyte counts are the best parameters to discriminate between both infections. A CRP value ≥ 3.27 mg/dl indicated the diagnosis of erysipelas with 75 % sensitivity and 73.2 % specificity.Conclusions: Our results support the thesis that erysipelas and limited cellulitis are distinct infections as defined in the German guidelines and that an assessment of CRP and leukocytes is useful for differential diagnosis.

The early inflammatory skin micromilieu affects resistance in experimental infection with Leishmania major. We pursue the concept that macrophages, which take up parasites during early infection, exert decisive influence on the inflammatory micromilieu after infection. In order to analyze their distinctive potential, we identified differentially regulated genes of murine granuloma macrophages (GMΦ) from resistant and susceptible mice after their infection with metacyclic Leishmania major. We found induction of several cytokines in GMΦ from both strains and a stronger upregulation of the transcription factor aryl hydrocarbon receptor (AhR) in GMΦ from resistant mice. Using both an AhR agonist and antagonist we demonstrated that AhR is involved in Leishmania-induced production of TNF in macrophages. In vivo, single local injection of an AhR agonist in early lesions of susceptible mice caused an increased induction of Tnf and other cytokines in the skin. Importantly, local agonist treatment led to a reduction of disease severity, reduced parasite loads and a weaker Th2 response. Our results demonstrate that local activation of AhR has a beneficial effect in experimental leishmaniasis.